In spite of major advances made in the past 20 years concerning the pathological anatomy, biochemical abnormalities and treatment of Parkinson's disease (PD), the pathophysiology of this disorder and how it is altered by therapy have remained enigmatic. Using the 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) primate model of parkinsonism, the long-range goals of this project are: (1) to elucidate the pathophysiology of the motor symptoms of PD and (2) to critically analyze how treatment alters motoric behavior and neuronal activity. Recent anatomical evidence1 indicates that the supplementary motor area (SMA) of the cerebral cortex is the major receiving site of basal ganglia output related to movement control in primates, and behavioral studies after lesions of the SMA in animals2,3 and man4-7 reveal motor deficits which are similar in many aspects to those seen in PD. A minor portion of SMA output projects directly to the spinal cord, providing the most direct pathway for expression of basal ganglia output, but the major projections from SMA are to the premotor (area 6) and precentral (area 4) motor cortical regions, both of which contribute heavily to the descending corticospinal and corticobulbar motor pathways. Hence, the SMA is poised in a pivotal position whereby it can serve as a major integrative site between basal ganglia output and other brain regions which are more directly involved in the control of movement. Therefore, the SMA will be studied using intracerebral single neuron recording techniques in awake monkeys trained to perform motor tasks with the upper limb, both in normal animals and before and after the induction of parkinsonism with MPTP. This will allow a quantitative correlation between alterations of neuronal discharge patterns in this cortical region and alterations of behavior associated with the parkinsonian state. At the end of the recording period the 2-deoxyglucose autoradiographic method8 will be applied under the same experimental conditions in order to correlate local metabolic activity with single unit activity, both in normal and parkinsonian monkeys. This aspect will provide an important parallel to positron emission tomographic (PET) and cerebral blood flow studies in normal and parkinsonian humans. Finally, the effects of treatment with levodopa and/or direct-acting dopamine receptor agonists will be analyzed in a group of the parkinsonian monkeys utilizing the same techniques under the same experimental conditions.